Lysosomal storage disorders (LSDs) are a heterogeneous group of inherited diseases with a collective frequency of 1 in 7,000 births. They result from a deficiency in one or more enzymes that normally reside within the lysosomes. These diseases typically affect multiple organ systems due to progressive accumulation of uncleaved lipids, glycoproteins and/or glycosaminoglycans and the resulting dysregulation of normal intra- and intercellular signalling pathways. LSDs are most often treated by life-long intravenous administration of recombinant replacement enzyme.


Gene therapy is based on the simple concept that providing a working copy of an appropriate gene to a patient should either stabilize or reverse clinical disease that has resulted from mutation or deletion of that gene. LSDs are attractive targets for gene therapy for several reasons: 1) each LSD is a single-gene recessive disorder and the pathophysiology of the diseases is relatively well understood; 2) studies in clinical patients have shown even small increases in enzyme activity may result in significant improvement in the clinical course of the disease; and 3) the “cross-correction” phenomenon suggests that successful transfection of only a small percentage of cells may be highly beneficial. Cross-correction simply means that lysosomal enzymes made by one cell are secreted in small amounts into the extracellular space where they can be taken up and targeted to lysosomes of neighboring cells and thus correct their dysfunction.


Gene therapy has already progressed to the clinic for several LSDs. Positive results from animal models provided the basis for a phase I/II clinical study in patients with Sanfilippo Syndrome A (mucopolysaccharidosis type IIIA) in which 4 patients were treated with intracerebral injections of a of a viral vector containing the gene for the missing enzyme (N-sulfoglucosamine sulfohydrolase). The treatment was safe and well tolerated and the patients showed moderate improvements in behavior, attention, and sleep. Gene therapy was employed to transfer functional copies of the arylsulfatase A gene to 3 presymptomatic patients with late infantile metachromatic leukodystrophy (MLD). Children affected with this disease begin having difficulty walking after the first year of life, and develop other symptoms, including muscle wasting and weakness, muscle rigidity, developmental delays, progressive loss of vision leading to blindness, convulsions, impaired swallowing, paralysis, and dementia. Untreated, most children with this form of MLD die by age 5. Gene transplantation in the 3 children with MLD was well tolerated and resulted in prevention of disease manifestations for up to 21 months beyond the predicted age of symptom onset. A second phase I trial using this approach confirmed these positive findings. These two examples clearly demonstrate the promise of gene therapy for patients with LSDs and raise the hope that it may become available for more patients with a wider range of these devastating diseases in the not distant future.

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